Discovery, Optimization, and Pharmacological Characterization of Novel Heteroaroylphenylureas Antagonists of C鈭扖 Chemokine Ligand 2 Function

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• 作者：Edgardo Laborde ; Robert W. Macsata ; Fanying Meng ; Brian T. Peterson ; Louise Robinson ; Steve R. Schow ; Reyna J. Simon ; Hua Xu ; Kunihisa Baba ; Hideaki Inagaki ; Yoshiro Ishiwata ; Takahito Jomori ; Yukiharu Matsumoto ; Atsushi Miyachi ; Takashi Nakamura ; Masayuki Okamoto ; Tracy M. Handel ; Claude C. A. Bernard
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1667-1681
• 全文大小：1195K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of ¹²⁵I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC₅₀ = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.